EP0292202A1

EP0292202A1 - 2-(3,4-Dihydroxyphenyl ethyl amines, their preparation and use as pharmaceutical compounds

Info

Publication number: EP0292202A1
Application number: EP88304319A
Authority: EP
Inventors: John Dixon; Francis Ince; Brian Springthorpe
Original assignee: Fisons Ltd
Current assignee: Fisons Ltd
Priority date: 1987-05-19
Filing date: 1988-05-12
Publication date: 1988-11-23
Anticipated expiration: 2008-05-12
Also published as: NO890187D0; US4939147A; PT87503A; WO1988009326A1; IL86411A; AU1706788A; US4922022A; FI890207A0; FI890207A; CA1294289C; JPH01503303A; NZ224676A; AU614749B2; EP0292202B1; NO890187L; EP0314725A1; IL86411A0; DE3874206D1; PT87503B

Abstract

There are described compounds of formula I,

in which
one of R₃₀ and R₄₀ represents a group Ra,

and the other of R₃₀ and R₄₀ represents hydrogen or halogen,
R₅₀ and R₆₀, which may be the same or different, each independently represent hydrogen or alkyl C 1 to C6; in addition R₆₀ may represent a group Rb,

wherein X represents a C2 to C8 alkylene chain optionally interrupted by a double bond or by S(0)_n, wherein n is 0, 1 or 2, Z represents a C 1 to C3 alkylene chain, each of X and Z being optionally substituted by OH or one or more alkyl C 1 to C6,
R₇₀ represents hydrogen, alkyl C 1 to C6 or (CH₂)_qR₁₁,
R₁₀ and R₁₁ independently represent phenyl substituted by one or more substituents R₂₃, which may be the same or different; or R₁₀ represents a saturated carbocyclic group,
R₁₅ represents hydrogen, alkyl C 1 to C6, or together with R₂₃ forms a (CH₂)p chain, wherein p represents 0, 1 or 2,
R₂₀, R₂₁, R₂₂ and R₂₃ independently represent hydrogen, alkyl C 1 to C6, NHR₂₅, SH, NO₂, halogen, CF₃, SO₂R₂₆, CH₂₀H or OH, wherein R₂₅ represents hydrogen, alkyl C 1 to C6 or alkanoyl C 1 to C6 and R₂₆ represents alkyl C 1 to C6 or NH₂
l represents 2, 3 or 4,
q represents an integer from 1 to 6 inclusive,
provided that when R₄₀, R₅₀ and R₇₀ each represent hydrogen and R₆₀ represents Rb,
then Ra represents 2(3-hydroxyphenyl)ethyl, R₁₅ represents hydrogen and either

a) X represents (CH₂)_p, in which p is 3, 5, 7 or 8 or
b) at least one of X and Z is substituted by either OH or one or more alkyl C 1 to C6,

and pharmaceutically acceptable salts and solvates thereof.

There are also described processes for the preparation of the compounds of formula I and pharmaceutical compositions containing them. The compounds of the invention may be used in the treatment or prophylaxis of renal failure or cardiovascular disorders.

Description

This invention relates to novel compounds, compositions thereof and processes for their preparation.
Catecholamine derivatives which may be used in the treatment or prophylaxis of renal failure or cardiovascular disorders are described in European Patent Application 0 223 598, which was published on 27.05.87 after the earliest priority date claimed in this application.
We have now found a novel group of catecholamine derivatives which may also be used in the treatment or prophylaxis of renal failure or cardiovascular disorders.
According to the invention there are provided compounds of formula I,
in which
one of R₃₀ and R₄₀ represents a group Ra,
and the other of R₃₀ and R₄₀ represents hydrogen or halogen,
R₅₀ and R₆₀, which may be the same or different, each independently represent hydrogen or alkyl C 1 to C6; in addition R₆₀ may represent a group Rb,
wherein X represents a C2 to C8 alkylene chain optionally interrupted by a double bond or by S(0)_n, wherein n is 0, 1 or 2, Z represents a C 1 to C3 alkylene chain, each of X and Z being optionally substituted by OH or one or more alkyl
C 1 to C6,
R₇₀ represents hydrogen, alkyl C 1 to C6 or (CH₂)_qR₁₁,
R₁₀ and R₁₁ independently represent phenyl substituted by one or more substituents R₂₃, which may be the same or different; or R₁₀ represents a saturated carbocyclic group,
R₁₅ represents hydrogen, alkyl C 1 to C6, or together with R₂₃ forms a (CH₂)p chain, wherein p represents 0, 1 or 2,
R₂₀, R₂₁, R₂₂ and R₂₃ independently represent hydrogen, alkyl C 1 to C6, NHR₂₅, SH, NO₂, halogen, CF₃, SO₂R₂₆, CH₂OH or OH, wherein R₂₅ represents hydrogen, alkyl C 1 to C6 or alkanoyl C 1 to C6 and R₂₆ represents alkyl C 1 to C6 or NH₂
l represents 2, 3 or 4,
q represents an integer from 1 to 6 inclusive,
provided that when R₄₀, R₅₀ and R₇₀ each represent hydrogen and R₆₀ represents Rb,
then Ra represents 2(3-hydroxyphenyl)ethyl, R₁₅ represents hydrogen and either

According to the invention, there is also provided a process for the preparation of compounds of formula I or pharmaceutically acceptable salts or solvates thereof, which comprises removing a protecting group from a corresponding compound of formula II,
in which
R₃₀a and R₄₀a have the same significance, respectively, as R₃₀ and R₄₀, save that in addition one of R₃₀a and R₄₀a may represent a group R_al,
R₅₀a has the same significance as R₅₀ above, save that in addition it may represent R₃a,
R₆₀a has the same significance as R₆₀ above, save that in addition it may represent a group R_bl,
in which
Xa and Za have the same significance, respectively, as X and Z above, save that in addition each may be substituted by OR₆a,
R₇₀a has the same significance as R₇₀ above, save that in addition it may represent R₄a or (CH₂)_qR₁₁a,
R₁₀a and R₁₁a have, respectively, the same significance as R₁₀ and R₁₁ above, save that when R₁₀a or R₁₁a represents phenyl, it may be substituted by one or more substituents R₂₃a,
R₁a, R₂a, R₃a and R₄a, which may be the same or different, represent hydrogen or a protecting group,
R₂₀a, R₂₁a R₂₂a and R₂₃a, respectively, have the same significance as R₂₀, R₂₁, R₂₂ and R₂₃ above, save that in addition they may represent NR₂₅R₂₇a, SR₂₈a, CH₂OR₂₉a or OR₃₁a, wherein R₂₇a, R₂₈a, R₂₉a and R₃₁a, which may be the same or different, each represents a protecting group, and R₁₅, R₂₅, l and q are as defined above, provided that the compound of formula II bears at least one protecting group,
and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable salt or solvate thereof, or vice versa.
Protecting groups that R₁a, R₂a, R₃a, R₄a, R₂₇a, R₂₈a, R₂₉a and R₃₁a may represent include, for example, alkyl C 1 to 6, especially methyl; phenylalkyl C7 to 12, especially benzyl; alkanoyl C2 to 6, such as acetyl and haloalkanoyl C2 to 6, especially trifluoroacetyl. In addition, the protecting group may protect two functional groups, for example R₂ and R₃ may together represent (CH₃)₂C
. Other protecting groups are well known and include those described in Protective Groups in Organic Chemistry, ed: J W F McOmie, Plenum Press (1973), and Protective Groups in Organic Synthesis, T W Greene, Wiley-Interscience (1981).
Removal of the protecting group depends on the nature of the protecting group; conventional techniques may generally be employed, including acidic or basic cleavage or hydrogenolysis. For example, protecting alkyl or phenylalkyl groups may be removed by cleavage using a protic acid, eg hydrochloric acid or a hydrobromic acid at a temperature of from about 0 to 150°C, or a Lewis acid, eg by reacting with boron trihalide in a halocarbon solvent. 1-Phenylalkyl groups, eg benzyl, may be removed by catalytic hydrogenation using a suitable catalyst, eg palladium, in a suitable solvent, eg methanol or acetic acid. Further methods for the removal of protecting groups are described in both McOmie and Greene, loc. cit. Both McOmie and Greene also describe numerous methods for the application of protecting groups.
Compounds of formula II in which X is interrupted by SO or SO₂ may be made from the corresponding compounds of formula II in which X is interrupted by S, by protection of the nitrogen atom(s) eg using trifluoracetic anhydride, oxidation, eg using m-chlorperbenzoic acid, and deprotection of the nitrogen atom(s).
Compounds of formula II in which R₆₀a represents a group R_bl may be made by reducing a corresponding compound of formula III,
in which R₁a, R₂a, R₁₅, R₁₀a, R₃₀a, R₄₀a, R₅₀a, R₇₀a, Xa and Za are as defined above.
The reducing agent may be electrophilic, for example diborane, or nucleophilic, for example, a complex metal hydride such as lithium aluminium hydride or sodium (2-methoxyethoxy)aluminium hydride. The reaction may be carried out in a suitable solvent inert to the reaction conditions. Aprotic solvents are preferred, for example tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. The reaction may be carried out at a temperature of, for example, from 0 to 100°C.
Compounds of formula III may be prepared by condensing a compound of formula IV,
in which R₃₅ represents OH, and R₁a, R₂a, R₃₀a, R₄₀a, R₅₀a and Xa are as defined above, with a compound of formula V,
HNR₇₀aCHR₁₅ZaR₁₀a V
in which R₁₀a, R₁₅, R₇₀a and Za are as defined above.
The condensation may be carried out under conditions similar to those used for the synthesis of peptide bonds in protein chemistry, eg by carrying out the reaction in the presence of N,N′-carbonyldiimidazole in a polar aprotic solvent or using a hindered base, eg triethylamine and an alkyl chloroformate. The condensation may also be carried out by reacting the acid chloride of the compound of formula IV with the compound of formula V.
Compounds of formula IV in which R₃₅ represents OH may be prepared from the corresponding compound of formula IV in which R₃₅ represents alkoxy by hydrolysis, eg using sodium hydroxide in water.
Compounds of formula IV in which R₃₅ represents alkoxy may be prepared by condensing a compound of formula VI,

in which R₁a, R₂a, R₃₀a, R₄₀a and R₅₀a are as defined above, with a compound of formula VII,
HO₂CXaCOalkoxy VII
in which Xa is as defined above.
The condensation may be carried out under conditions analogous to those described above for the preparation of compounds of formula III.
The compounds of formula III may also be prepared by condensing a compound of formula VI with a compound of formula VIII,
HO₂CXaCONR₇₀aCHR₁₅ZaR₁₀a VIII
in which Xa, Za, R₁₀a, R₁₅ and R₇₀a are as defined above.
The condensation may be carried out under conditions analogous to those described above.
Compounds of formula II, in which one or both of R₅₀a and R₆₀a represent alkyl C 1 to C6 may be prepared by conventional alkylation of a compound of formula VI, in which R₅₀a represents hydrogen or a protecting group,
in which R represents hydrogen or halogen and R₁a, R₂a and Ra are as defined above.
Esters of the benzoic acid IX may also be prepared by processes analogous to the following route:
in which R₁a, R₂a, R, R₂₀a, R₂₁a and R₂₂a are as defined above.
Other routes for the preparation of compounds of formula VI, in which R₅₀a represents hydrogen, are described in the Examples.
The compounds of formulae V, VII, VIII, X, XI and XII are either known or may be made from known compounds using conventional techniques known per se.
Acid addition salts of compounds of formula I may be converted to the corresponding free-base by the action of a stronger base. The acid addition salts of the compound of formula I may be prepared by reaction of the free base with an appropriate acid.
Pharmaceutically acceptable acid addition salts of the compounds of formula I include salts of mineral acids, for example, hydrohalic acids, eg hydrochloric or hydrobromic acid; or organic acids, eg formic, acetic or lactic acids. The acid may be polybasic, for example sulphuric, fumaric or citric acid.
Solvates of the compounds of formula I and their salts include hydrates, in particular hydrates of the salts of formula I, eg hemihydrates, monohydrates and sesquihydrates.
We prefer compounds of formula I in which R₃₀ represents Ra.
We prefer compounds of formula I in which R₄₀ represents hydrogen.
We prefer compounds of formula I in which R₅₀ represents hydrogen and more preferably compounds in which both R₅₀ and R₆₀ are hydrogen.
We prefer compounds of formula I in which R₁₀ represents phenyl substituted by one or more substituents R₂₃. We prefer R₁₀, when it represents phenyl, to be substituted by hydrogen or by one, two or three substituents other than hydrogen. Preferred groups that R₂₃ may represent include hydrogen, halogen, eg fluorine or chlorine; hydroxy, NH₂, NHsO₂alkyl C 1 to 6, NO₂ or alkyl C 1 to 6, eg methyl or ethyl. We particularly prefer compounds in which R₁₀ is substituted by one or more hydroxy groups, eg 4-OH. Groups that R₁₀ may particularly represent include halodihydroxyphenyl, eg fluoro-dihydroxyphenyl; halohydroxyphenyl, eg fluorohydroxyphenyl; hydroxyphenyl, eg 3- or 4-hydroxyphenyl; dihydroxyphenyl, eg 3,4-dihydroxyphenyl or 2,3-dihydroxyphenyl.
When R₁₀ represents a saturated carbocyclic group, preferred carbocyclic groups include those with 5 to 7 inclusive ring atoms, especially six, ie cyclohexyl.
When R₁₅ together with R₂₃ forms a chain, the group CHR₁₅(CH₂)_m-1R₁₀ may represent 2-(1,2,3,4-tetrahydronaphthalenyl), 1-(benzcyclobutenyl) or especially 2-indanyl.
Alkyl groups that R₁₀ may represent include methyl, ethyl, propyl or butyl.
We prefer compounds of formula I in which R₂₀, R₂₁ and R₂₂ independently represent hydrogen, hydroxy, alkyl C 1 to 6, eg methyl or ethyl; halogen, eg chlorine or fluorine, or trifluoromethyl
Compounds of formula I that may particularly be mentioned include those in which at least one of R₂₀, R₂₁ and R₂₂ represents hydroxy. We particularly prefer compounds in which one of R₂₀, R₂₁ and R₂₂ represents 3-hydroxy. Compounds that may also be specifically mentioned include those in which two of R₂₀, R₂₁ and R₂₂ represent hydroxy.
We prefer compounds of formula I in which X represents a C3 to C7, more preferably a C4 to C6 inclusive alkylene chain.
We prefer compounds of formula I in which l represents 2 or 3, especially 2.
We prefer compounds of formula I in which Z represents (CH₂)₂ and especially CH₂.
The compounds of formula I, and pharmaceutically acceptable acid addition salts thereof, are useful because they possess pharmacological activity in animals. Thus the compounds act on peripheral and/or central dopamine receptors. As such, they lower blood pressure and increase blood flow to certain vascular beds, eg renal beds. Activity of the compounds has been investigated in the following assay systems:

(a) canine renal blood flow, McNay and Goldberg, J. Pharmac, Exp. Ther., 151, 23-31, 1966.
(b) rabbit isolated ear artery, McCullogh, Rand and Story, Br. J. Pharmac, 49, 141-142, 1973.
(c) guinea pig tracheal chains, Akcasu, Arch. Int. Pharmacodyn. Ther., 122, 201-207, 1959.
(d) guinea pig atria: O'Donnell and Wanstall, J. Pharm. Pharmacol., 31, 686-690, 1979.

The compounds of the invention are indicated for use in the treatment of congestive heart failure, renal failure, angina pectoris, ischaemic heart disease and hypertension. The compounds of the invention are also indicated for use in the treatment of shock and other low cardiac output states of varying aetiology, acute cerebrovascular disease and improvement of the blood supply to and healing of intestinal anastomoses and stomata.
The dosage administered will naturally depend on the compound employed, the mode of administration and the desired effect. However, in general, satisfactory results are obtained when the compound is administered at a dosage of from 0.05 µg to 50mg per kilogram of body weight per day. For man, the indicated total daily dosage is in the range 2.5 µg to 3.5g, which may be administered in divided doses of, for example 1 µg to 750mg.
The compounds of formula I, and pharmaceutically acceptable derivatives thereof, have the advantage that they are more efficacious or produce less undesirable side effects in certain pharmacological models than compounds of similar structure to the compound of formula I.
The compound of the invention may be administered by a wide variety of routes and may act systemically or locally. Thus the compound may be administered by oral or nasal inhalation to the lung, to the buccal cavity, oesophageally, rectally, topically to the skin or to other available surfaces of the body, eg the eye, by injection, eg intravenously, intramuscularly, intraperitoneally, by instillation or by surgical implant.
According to our invention we also provide a pharmaceutical composition comprising preferably less than 80%, and more preferably less than 50%, by weight of a compound of formula I, or a pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Examples of suitable adjuvants, diluents or carriers are: for tablets, capsules and dragees; microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin;
for suppositories; natural or hardened oil or waxes; and
for inhalation compositions, coarse lactose.
When the compound is to be used in aqueous solution it may be necessary to incorporate a chelating or sequestering agent, eg sodium edetate, an antioxidant, eg sodium metabisulphite or buffering agents, eg sodium hydrogen phosphate and sodium phosphate. Aqueous solutions typically contain up to about 10% w/w of the new compound and may be used for intravenous injections.
According to the invention, we further provide a method of treatment of acute renal failure in an animal, either human or non-human, which method comprises administering to the animal an effective amount of the compound of the invention or a pharmaceutically acceptable acid addition salt thereof.
The invention is illustrated, but in no way limited, by the following Examples in which temperatures are in degrees Centigrade.

A. Preparation of Intermediates

1. Preparation of 4,4-dimethyloxazoles

a) 2-[3,4-Dimethoxy-2-(2-[3-methoxyphenyl]ethyl)phenyl]-4,5-dihydro-4,4-dimethyloxazole

A solution of 2-[3-methoxyphenyl]ethylbromide (12.2g) in dry tetrahydrofuran (20ml) was added dropwise to a suspension of magnesium (1.46g) in dry tetrahydrofuran (20ml), under an atmosphere of nitrogen, at a rate sufficient to maintain a state of reflux. After 1 hour the cooled solution was added to a stirred solution of 4,5-dihydro-4,4-dimethyl-2-[2,3,4-trimethoxyphenyl] oxazole (7.95g) in dry tetrahydrofuran (50ml) under an atmosphere of nitrogen. The mixture was stirred at 20° for 16 hours. Water (400ml) was added and the aqueous phase thoroughly extracted with ethyl acetate (2 x 250ml). The organic phase was dried over magnesium sulphate, filtered and the solvent removed in vacuo to yield a yellow oil which was purified by flash column chromatography on silica gel, using 10% ethyl acetate/90% petroleum ether as eluent, and by Kugelruhr distillation (air bath temperature 200°/1mm Hg) 9.7g of the sub-title compound were obtained, ms m/e 369.
Similarly prepared were:

b) 2-[3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole, ms m/e 369;
c) 2-[3,4-Dimethoxy-2-[2-phenylethyl]phenyl]-4,5-dihydro-4,4-dimethyloxazole, ms m/e 339;
d) 2-[3,4-Dimethoxy-2-[2-[3,4-dimethoxyphenyl]ethyl] phenyl]-4,5-dihydro-4,4-dimethyloxazole, ms m/e 399;
e) 2-[5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]-4,5-dihydro-4,4-dimethyloxazole, mp 95-98°;
f) 2-[5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl] phenyl]-4,5-dihydro-4,4-dimethyloxazole, m/e 403/405;
g) 2-[4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethylphenyl]-4,5-dihydro-4,4-dimethyloxazole, m/e 369.

2. Preparation of benzoic acids

a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzoic acid

A solution of the product from Intermediate 1 a) (9.7g) in excess methyl iodide (10ml) was heated at reflux temperature for 4 hours. Dry ether (100ml) was added and the resulting precipitate filtered to yield 11g of the oxazolinium salt which was used without further purification.
A solution of this oxazolinium salt (11g) in 20% aqueous sodium hydroxide (200ml) and methanol (200ml) was heated at reflux temperature for 6 hours. The cooled solution was acidified and the solid filtered, dried and crystallised from isopropanol to yield the sub-title compound (6.2g) as colourless prisms, mp 156-158°.
Similarly prepared were:

b) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl]benzoic acid, mp 148-150°;
c) 3,4-Dimethoxy-2-[2-phenylethyl]benzoic acid, mp 142-144°;
d) 2-[2-[3,4-Dimethoxyphenyl]ethyl]-3,4-dimethoxy benzoic acid, mp 148-149°.
e) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzoic acid, mp 123-125°;
f) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl] benzoic acid, mp 96-98°;
g) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzoic acid, mp 152-155°.

3. Preparation of benzenemethanols

Method A

a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzene methanol

A solution of the product from Intermediate 2 a) (6.2g) in dry tetrahydrofuran (50ml) was stirred under an atmosphere of nitrogen during the addition of 40ml of a 1M solution of borane in tetrahydrofuran complex. The mixture was heated under reflux for 3 hours, cooled and methanol (80ml) added. The solution was evaporated to dryness, dissolved in ethyl acetate and washed with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulphate, filtered and the solvent removed in vacuo to leave a solid which was crystallised from isopropanol to yield 5.2g of the sub-title compound as colourless flakes, mp 108-109°
Similarly prepared were:

b) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl] benzenemethanol, mp 83-85°;
c) 3,4-Dimethoxy-2-[2-phenylethyl]benzenemethanol, mp 99-100°;
d) 2-[2-[3,4-Dimethoxyphenyl]ethyl]3,4-dimethoxy benzenemethanol, mp 103.5-105.5;
e) N-[3-[2-[2,3,-Dimethoxy-6 hydroxymethylphenyl]ethyl] phenyl]methanesulphonamide, mp 113-115°;
f) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzenemethanol, mp 54-56°;
g) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl] benzenemethanol, m/e 408;
h) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzenemethanol, m/e 302.

Method B

a) 2-[2-[3,5-Dimethoxyphenyl]ethyl]3,4-dimethoxybenzene methanol

A 1M solution of lithium aluminium hydride in tetrahydrofuran (80ml) was added dropwise to a stirred solution of the intermediate ester from step 7Bb (20g) in dry tetrahydrofuran under a nitrogen atmosphere at -78° The solution was stirred at 20° for 2 hours. The mixture was quenched with brine (10ml) and evaporated to dryness. The residue was partitioned between ether and 2N hydrochloric acid and separated. The organic solution was washed with brine, dried (MgSO₄), filtered and evaporated to give a solid. Crystallisation from isopropanol gave 15g of the intermediate alcohol as colourless flakes, mp 126-128°.
Similarly prepared were:

b) 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethyl] benzenemethanol, mp 132.5-134°;
c) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl] benzenemethanol, m/e 302.

Method C

a) E-3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethenyl] benzenemethanol

A 1.5M solution of diisobutylaluminium hydride in toluene (50ml) was added dropwise to a stirred solution of the ethenyl ester from step 7Bal (14.6g) in dry tetrahydrofuran (120ml). The solution was stirred at 20° for 1 1/2 hours. The solution was evaporated and the residue quenched slowly with 2N hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with brine, dried (MgSO₄), filtered and evaporated to give a solid which crystallised from isopropanol to give 9.64g of the alcohol as colourless flakes, mp 119.5-121°.

Method D

a) 3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethyl] benzenemethanol

A 0.5M solution of Aluminium hydride in tetrahydrofuran (56ml) was added dropwise to a solution of the intermediate 7Ba2 (5.06g) in dry tetrahydrofuran (50ml). The solution was stirred at 20° for 16 hours. The solution was quenched with water and extracted with ethyl acetate. The organic phase was dried (MgSO₄), filtered and evaporated. The residue was purified by flash chromatography (Merck 9385 silica gel) eluting with ethyl acetate/60/80 petrol ether (1:1) to give the alcohol as a colourless solid (3.21g).

4. Preparation of benzeneacetonitriles

a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzenacetonitrile

A solution of the alcohol from Intermediate 3 a) (5g) and thionyl chloride (1.5ml) in dry dichloromethane (50ml) was heated at reflux temperature for 3 hours. The solution was evaporated to dryness.
The cooled crude chloride was dissolved in dry dimethylsulphoxide (25ml). Powdered sodium cyanide (1.5g) was added to the solution and the mixture was stirred at 20° for 16 hours. Brine (150ml) was added and the mixture extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate, filtered and evaporated on a steam bath until HCN had ceased to be evolved. Further evaporation gave a yellow solid which was crystallised from isopropanol to yield 4.0g of the sub-title compound as prisms, mp 98-100°.
Similarly prepared were:

b) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl] benzeneacetonitrile, mp 91-93°;
c) 3,4-Dimethoxy-2-[2-phenylethyl]benzeneacetonitrile, ms m/e 287;
d) E-3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethenyl] benzeneacetonitrile, mp 134-136°;
e) 3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethyl] benzeneacetonitrile, mp 112-115°;
f) N-[3-[2-[2,3-Dimethoxy-6-cyanomethyl]phenyl]ethyl] phenyl]methane sulphonamide, mp 111-112°;
g) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzeneacetonitrile, mp 70-72°;
h) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl] benzeneacetonitrile, mp 95-96°;
i) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzeneacetonitrile, mp 71-73°;
j) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl] benzeneacetonitrile, m/e 311.

5. Preparation of intermediates of formula VI in which R₅₀a is hydrogen

a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzeneethanamine hydrochloride

A solution of the nitrile from Intermediate 4 a) (4g) in dry tetrahydrofuran (50ml) was stirred under an atmosphere of nitrogen during the addition of a 1M solution of borane in tetrahydrofuran (25.7ml). The mixture was heated at reflux temperature for 2 hours. Methanol (40ml) was added to the cooled reaction mixture and the solution evaporated to dryness. The residue was dissolved in methanol (50ml) and conc. hydrochloric acid (5ml) added. The mixture was heated at reflux temperature for 1 hour and then the solution was evaporated to dryness to yield a beige solid. This was treated with dilute sodium hydroxide solution to yield 2-[2-(3-methoxyphenyl) ethyl-3,4-dimethoxybenzeneethanamine which was purified by flash column chromatography on silica gel using 90% chloroform/10% methanol as eluent. The resulting oil was treated with ethereal HCl to give 1.2g of the sub-title compound as colourless prisms after crystallisation from isopropanol, mp 164-166°
Similarly prepared were:

b) 3,4-Dimethoxy-2-[2-[4-methoxyphenyl]ethyl] benzeneethanamine hydrochloride, mp 135-137°;
c) 3,4-Dimethoxy-2-[2-phenylethyl]benzeneethanamine hydrochloride, mp 201-203°;
d) 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethyl] benzeneethanamine hydrochloride, softens 105-110°, mp 158.5-159.5°;
e) 3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethyl] benzeneethanamine hydrochloride, mp 228-230°;
f) N-[3-[2-[2,3-Dimethoxy-6-[2-aminoethyl]phenyl]ethyl] phenyl]methanesulphonamide hydrochloride, mp 181-183°.
g) 5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzeneethanamine hydrochloride, mp 147-149°;
h) 5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl]ethyl] benzeneethanamine hydrochloride, mp 197-199°;
i) 4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzeneethanamine hydrochloride, mp 178-179°;
j) 3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl] benzeneethanamine hydrochloride, m/e 315.

6. Preparation of diamide intermediates of formula III from intermediates of formula VI and intermediates of formula VIII

a) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethylphenyl] ethyl]-N′-[2-phenylethyl]heptane-1,7-diamide

A solution of the acid intermediate from 9 a) (1.87g) and N,N-carbonyldiimidazole (1.3g) in dry dichloromethane (50ml) was stirred at 20° under nitrogen for 2 hours and a solution of 3,4-dimethoxy-2-[2-[3-methoxyphenyl]ethyl]benzeneethanamine (2.24g) in dry dichloromethane (20ml) was then added. The mixture was stirred at 20° for 16 hours. The solution was quenched with 2N hydrochloric acid and separated. The organic phase was washed with saturated sodium bicarbonate solution, water, dried (MgSO₄), filtered and evaporated to leave a sticky solid. Trituration with ether gave a colourless solid which was filtered and dried (3.25g), mp 103-108°
Similarly prepared were:-

b) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]nonane-1,9-diamide, mp 116-118°;
c) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]decane-1,10-diamide, mp 133-135°;
d) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]-3-methylpentane-1,5-diamide, softens 112°, mp 133-135°;
e) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]methoxy-N′-[2-phenylethyl]-3,3-dimethylpentane-1,5-diamide, ms m/e 560;
f) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]pentane-1,5-diamide, mp 132-134°;
g) N-[2-[5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl] ethyl]phenyl]ethyl]-N′-[2-phenylethyl]hexane-1,6-diamide, mp 145-147°;
h) N-[2-[5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl] ethyl]phenylethyl]-N′-[2-phenylethyl]hexane-1,6-diamide, mp 135-137°;
i) N-[2-[3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]hexane-1,6-diamide, mp 122-124°;
j) N-[2-[4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]hexane-1,6-diamide, mp 135-136°;
k) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-methyl-N′-[2-phenylethyl]hexane-1,6-diamide, oil, m/e 560;
1) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]phenyl ]ethyl]-N′-N′-di[2-phenylethyl]hexane-1,6-diamide, mp 97-99°;
m) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-[4-methoxyphenyl]ethyl]-N′-[2-phenylethyl]hexane-1,6-diamide, oil, m/e 681.

7. Alternative route for the preparation of benzene methanols, via Wittig reaction Phosphonium salt formation

a) Ethyl 3,4-dimethoxy-2-methyl benzoate

A solution of 3,4-dimethoxy-2-methylbenzoic acid (5.9g) in ethanol (200ml) containing concentrated hydrochloric acid (10ml) was heated at reflux temperature for 16 hours. The cool solution was evaporated down to an oil then dissolved in ether. The organic solution was washed with 1N sodium hydroxide solution (100ml), brine (100ml), dried (MgSO₄), filtered and evaporated to leave a solid.
The solid was purified by flash chromatography eluting with 60/80 petrol ether/ethyl acetate (10:1) to give the sub-title ester as colourless needles (6.58g), mp 46-49°.

b) Ethyl 2-bromomethyl-3,4-dimethoxybenzoate

A solution of the ester (stage a) (67.2g), N-bromosuccinimide (57g) and azobisisobutyronitrile (catalytic) in carbontetrachloride (700ml) was heated under reflux under irradiation (60w bulb) for 2 1/2 hours. The cooled reaction was washed with water.
The organic solution was dried (MgSO₄), filtered and evaporated to leave a solid. The solid was purified by flash chromatography (Merck 9385 silica gel) eluting with dichloromethane /60/80 petrol ether (1:1). Evaporation of the required fractions gave a yellow solid (84.1g), ms m/e 302/304.
Similarly prepared was:
b.1) 2-[2-Bromomethyl 3,4-dimethoxyphenyl]-4,5-dihydro-4,4-dimethyloxazole, ms m/e 327/329.

6-Ethoxycarbonyl-2,3-dimethoxyphenyl]methyltriphenyl phosphonium bromide

A solution of the product of step b) (83.9g) and triphenylphosphine (72.55g) in toluene (500ml) was heated under reflux in a nitrogen atmosphere for 24 hours. The precipitate from the cooled solution was filtered, slurried with ether and stirred for 2 hours. The solid was filtered and dried (129g), mp 198-200°.
Similarly prepared was:
c.1) [6-[4,5-Dihydro-4,4-dimethyloxazole-2-yl]-2,3-dimethoxyphenyl]methyltriphenylphosphonium bromide, ms m/e 510 (cation)

Variation A - oxazole route

Wittig reaction

Aa) E-2-[3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethenyl]phenyl] 4,5-dihydro-4,4-dimethyloxazole

A solution of the phosphonium bromide from step c.1) (69g) in dry dimethylformamide (300ml) was added dopwise to a suspension of 80% sodium hydride (3.51g) stirred in dry dimethylformamide (100ml) at 0° under a nitrogen atmosphere. The mixture was stirred for 30 minutes at 60° and a solution of 3-nitrobenzaldehyde (17.7g) in dry dimethylformamide (100ml) was then added.
The mixture was stirred at 20° for 1 hour then quenched with ice/water.
The solid mass was extracted into ethyl acetate and separated. The organic solution was washed with water, dried (MgSO₄), filtered and evaporated to give a yellow oil which was purified by flash chromatogarphy (Merck 9385 silica gel) eluting with dichloromethane/ethyl acetate (95:5). Evaporation of the relevant fractions gave the sub-title compound as pure E isomer (35g), mp 78-80°.

Reduction of nitro group

Ab) E-3-[2-[6-4,5-Dihydro-4,4-dimethyloxazole-2-yl]-2,3-dimethoxyphenyl]ethenyl]benzeneamine

A solution of the nitro intermediate Aa) (32g) in ethanol (250ml) was hydrogenated over a platinum oxide catalyst (0.3g) at 2 atmospheres for 2 hours. The catalyst was removed by filtration and the filtrate evaporated to leave a colourless solid (26.5g), ms m/e 352.

Sulphonamide formation and cleavage of oxazole

Ac) E-3,4-Dimethoxy-2-[2,[3-[methanesulphonylamino]phenyl] ethenyl]benzoic acid

Methanesulphonylchloride (12.4ml) was added dropwise to a stirred solution of the benzenamine Ac) (26.5g) and triethylamine (24ml) in dry dichloromethane (200ml). The solution was stirred at 20° for 1 hour. The solution was washed with water, dried (MgSO₄), filtered and evaporated to leave 29g of the dimethanesulphonamide intermediate.
A solution of this intermediate in methyliodide (50ml) and dichloromethane (200ml) was heated at reflux temperature for 2 days. The solution was evaporated and the residue triturated with ether to give 41g of the quaternary salt as a yellow solid, mp 193°.
A solution of the quaternary salt in methanol (800ml) and 10% sodium hydroxide solution (160ml) was heated to reflux temperature for 3 hours. The solution was evaporated and acidified with 2N hydrochloric acid. The solid precipitate was filtered, washed with water and dried. The solid crystallised from ethanol to give 20.5g of the acid as a colourless solid, mp 221-223°.

Reduction of double bond

Ad) 3,4-Dimethoxy-2-[2-[3-[methanesulphonyl]aminophenyl] ethyl]benzoic acid

A solution of the acid Ac) (8.15g) in 1M sodium hydroxide solution (200ml) was hydrogenated over a 10% palladium on charcoal catalyst (2g) at 3 atmospheres and 45° for 18 hours. The catalyst was removed by filtration and the cooled solution acidified with 2N hydrochloric acid. The solid was dissolved in ethyl acetate and separated. The organic solution was washed with water, dried (MgSO₄), filtered and evaporated to leave a solid. Crystallisation from ethylacetate/petrol gave 6.26g of the acid as a colourless powder, mp 187.5-188.5°.

Variation B - benzoate ester route

Wittig reaction

Ba) E/Z-Ethyl-2-[2-[3,5-Dimethoxyphenyl]ethenyl] 3,4-dimethoxy benzoate

A 1.6M solution of butyl lithium in hexane (55ml) was added dropwise to a stirred suspension of the phosphonium salt (45.2g) from step 7 c) in dry tetrahydrofuran (200ml) under a nitrogen atmosphere at 0°. The mixture was stirred at 0° for 1 hour and a solution of 3,5-dimethoxybenzaldehyde added. The resulting mixture was stirred at 20° for 16 hours.
The mixture was quenched with brine (50ml) and evaporated to dryness. The solid was dissolved in ethyl acetate washed with brine, dried (MgSO₄), filtered and evaporated to give a dark oil. The oil was purified by flash chromatography (Merck 9385 silica gel) eluting with dichloromethane/petrol 60/80 (1:1) to give 24g of the intermediate ester as a colourless oil, ms m/e 372.
Similarly prepared were:

Ba.1) E-Ethyl 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl] ethenyl]benzoate, mp 103-104°;
Ba.2) E/Z-Ethyl 3,4-Dimethoxy-2-[2-[3-nitrophenyl]ethenyl] benzoate, mp 80-82°.
Ba.3) Ethyl 3,4-dimethoxy-5-[2-[3-methoxyphenyl]ethenyl] benzoate, m/e 342.

Reduction of double bond

Bb) Ethyl-2-[2-[3,5-Dimethoxyphenyl]ethyl]3,4-dimethoxy benzoate

A solution of the intermediate ethenyl ester Ba) (24g) in ethanol (150ml) was hydrogenated over a 10% palladium on charcoal catalyst (1g) at atmospheric pressure for 24 hours. The catalyst was removed by filtration and the filtrate evaporated to leave a yellow oil. The oil was purified by flash chromotography (Merck 9385 silica gel) eluting with 60/80 petrol ether/10% ethyl acetate to give 20g of the intermediate ester as a colourless oil, ms m/e 374.
Similarly prepared were:

Bb.1) Ethyl 3,4-dimethoxy-2-[2-[3,4,5-trimethoxyphenyl] ethyl]benzoate, ms m/e 440;
Bb.2) 3,4-Dimethoxy-2-[2-[3,4,5-trimethoxyphenyl]ethyl] benzeneacetonitrile, mp 119.5-120.5°;
Bb.3) Ethyl 3,4-dimethoxy-5-[2-[3-methoxyphenyl]ethyl] benzoate, ms m/e 344.

Selective reduction of the double bond of the intermediate Ba.2

Bc) Ethyl-3,4-dimethoxy-2-[2-[3-nitrophenyl]ethyl]benzoate

A solution of the ethenyl ester Ba.2) (5g) in benzene (100ml) was hydrogenated over Wilkinson's catalyst at 65 atmospheres for 48 hours.
The mixture was evaporated to dryness and purified by flash chromatography (Merck 9385 silical gel) eluting with ethylacetate/60/80 petrol ether (1:3) to give the ester as a colourless powder (4.83g).

8. Alternative routes to benzeneethanamines

a) 2-[2-[3,5-Dimethoxyphenyl]ethyl]3,4-dimethoxy benzaldehyde

A solution of the intermediate alcohol 3 Ba) (13.3g) in dry dichloromethane containing activated manganese dioxide (60g) was vigourously stirred at 20° for 2 hours. The suspension was filtered and the filtrate evaporated to give 13.2g of the aldehyde as a white solid, mp 88-89°.
Similarly prepared was:
2-[2-[3,4-dimethoxyphenyl]ethyl]-3,4-dimethoxy benzaldehyde, ms m/e 330.

b)3-[2-[3,5-Dimethoxyphenyl]ethyl]-1,2-dimethoxy-4-[E-2-nitroethenyl]benzene

A solution of the aldehyde 8 a) (10.8g) in n-butylamine (15ml) was heated at 110° for 2 hours. The solution was evaporated, dissolved in ether, dried (MgSO₄), filtered and evaporated to give 12.1g of the butylimine as a solid, mp 67-68°.
A solution of the imine (12.1g) and nitromethane (4ml) in glacial acetic acid was heated at 100° for 4 hours. The solution was evaporated and the residue dissolved in ethyl acetate. The organic solution was washed with brine, dried (MgSO₄), filtered and evaporated. Crystallsation from isopropanol gave 10.8g of the nitrostyrene as yellow prisms, mp 110-112°.
Similarly prepared was:
b.1) 3-[2-[3,4-Dimethoxyphenyl]ethyl]-1,2-dimethoxy-4-[E-2-nitroethenyl]benzene, mp 95-96°

Reduction - Method A:

c) 2-[2-[3,5-Dimethoxyphenyl]ethyl]-3,4- dimethoxybenzeneethanamine

A 1M solution of lithium aluminium hydride in tetrahydrofuran (60ml) was added dropwise to a stirred solution of the nitro compound b) (3.7g) in dry tetrahydrofuran under a nitrogen atmosphere. The solution was stirred at 20° for 24 hours. The cooled solution was treated with 2N sodium hydroxide solution until precipitation was complete. The solid mass was extracted with warm ethyl acetate. The organic solution was dried (MgSO₄), filtered and evaporated to leave a yellow oil. Trituration with ethereal hydrogen chloride gave a pink solid (2.6g).
This was purified by reverse phase semi preparitive HPLC (Dynamx 60A SiO₂ column) eluting with water with 0.1% trifluoroacetic acid/methanol (50:50). Evaporation of the relevant fractions gave an oil which was basified with 10% sodium hydroxide solution and extracted into ethyl acetate. The organic solution was dried (MgSO₄), filtered and evaporated to leave a colourless oil. Trituration with ethereal hydrogen chloride gave a solid which crystallised from isopropanol to give 1.35g of the sub-title compound as the hydrochloride salt, mp 179-180°.

Reduction - Method B:

d) 2-[2-[3,4-Dimethoxyphenyl]ethyl]-3,4- dimethoxybenzeneethanamine

Sodium borohydride (2.8g) was added portionwise over 10 minutes to a stirred suspension of the nitrostyrene b.1) (5.6g) and silica gel (Fluka 60) (28g) in chloroform (200ml) and isopropanol (50ml). The suspension was stirred at 20° for 16 hours. The silica gel was removed by filtration and the solvent evaporated to dryness to give the intermediate nitroethane as a pale yellow oil.
A solution of the oil in ethanol (100ml) was hydrogenated over a platinum oxide catalyst (20mg) at 3 atmospheres and 45° for 7 days.
The catalyst was removed by filtration and the filtrate evaporated. Trituration with ethereal hydrogen chloride gave a grey solid. This was purified by reverse phase HPLC (Dynamax 60A SiO₂ column) eluting with water with 0.1% trifluoroacetic acid/methanol (55:45). Evaporation of the relevant fractions gave an oil which was basified with 10% sodium hydroxide solution and extracted into ethyl acetate. The organic solution was dried (MgSO₄), filtered and evaporated to leave a colourless oil. Trituration with ethereal hydrogen chloride gave a solid which crystallised from isopropanol to give 1.3g of the sub-title compound as the hydrochloride salt, mp 152-153°.

9. Preparation of intermediates of formula VIII

a) 7-Oxo-7-[2-phenylethylamino]heptanoic acid

A solution of monomethylpimelate (5.0g) and N,N-carbonyldiimidazole (4.9g) in dry dichloromethane (200ml) was stirred under nitrogen at 20° for 2 hours and a solution of 2-phenylethylamine (3.22g) in dry dichloromethane (100ml) was then added. The mixture was stirred at 20° for 16 hours. The solution was quenched with 2N hydrochloric acid (50ml) and separated. The organic solution was washed with water, dried (MgSO₄), filtered and evaporated to leave the intermediate ester as a solid (7.05g).
A solution of the ester (7.0g) in methanol (100ml) and 20% sodium hydroxide solution (15ml) was heated to reflux temperature for 3 hours. The solution was evaporated and the residue acidified with 2N hydrochloric acid. The solid mass was dissolved in ethyl acetate (400ml), washed with water (2x100ml), dried (MgSO₄), filtered and evaporated. Crystallisation from ethyl acetate gave the sub-title acid intermediate as colourless prisms (5.7g), mp 78-79°.
Similarly prepared were:-

b) 9-Oxo-9-[2-phenylethylamino]nonanoic acid, mp 97.5-99°;
c) 10-Oxo-10-[2-phenylethylamino]decanoic acid, mp 108.5-109.5°;
d) 6-Oxo-6-[N-methyl-N-2-phenylethylamino]hexanoic acid, mp 95-97°;
e) 6-Oxo-6-[[N-2-phenylethyl]-2-phenylethylamino] hexanoic acid, m/e 353;
f) 6-Oxo-6-[[N-2-[4-methoxyphenyl]ethyl]-2-phenylethylamino]hexanoic acid, m/e 383.

g)3-Methyl-5-oxo-5-[2-phenylethylamino]pentanoic acid

A solution of 2-phenylethylamine (6.3ml) in dry toluene (50ml) was added dropwise to a stirred solution of 3-methylglutaric anhydride (6.4g) in dry toluene (250ml) at 0° under a nitrogen atmosphere. After complete addition the mixture was heated at reflux temperature for 3 hours. The solution was evaporated and the residual oil triturated with ether (150ml). The solid was filtered and dried to give the sub-title intermediate (3.3g), mp 78-80°.
Similarly prepared were:-

h) 3,3-Dimethyl-5-oxo-5-[2-phenylethylamino]pentanoic acid, ms m/e 263;
i) 5-Oxo-5-[2-phenylethylamino]pentanoic acid, mp 83.5-85°.

10. Preparation of intermediates of formula II by reduction of intermediates of formula III

a) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethylphenyl] ethyl]-N′-[2-phenylethyl]heptane-1,7-diamine

A solution of the diamide of step 6 a) (3.11g) in dry tetrahydrofuran (30ml) was stirred under an atmosphere of nitrogen during the addition of a 1M solution of borane in tetrahydrofuran (30ml). The mixture was heated at reflux temperature for 18 hours. Methanol (50ml) was added to the cooled solution and the mixture evaporated to dryness. The residue was dissolved in methanol (100ml) and concentrated hydrochloric acid (10ml) added. The mixture was heated under reflux for 2 hours. The solution was evaporated to give a solid which crystallised from isopropanol to give (2.88g) of the dihydrochloride salt of the title compound as colourless prisms, mp 227-229°.
Similarly prepared were:-

b) N-[2-[3,4-Dimethoxy-2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]nonane-1,9-diamine dihydrochloride, mp 173-175°;
c) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]decane-1,10-diamine dihydrochloride, mp 178-180°;
d) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]-3-methylpentane-1,5-diamine dihydrochloride, mp 241-243°;
e) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]-3,3-dimethylpentane-1,5-diamine dihydrochloride, mp 157-159°;
f) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]pentane-1,5-diamine dihydrochloride, mp 242-244°;
g) N-[2-[5-Chloro-3,4-dimethoxy-2-[2-[3-methoxyphenyl] ethyl]phenyl]ethyl]-N′-[2-phenylethyl]hexane-1,6-diamine dihydrochloride, mp 234-236°;
h) N-[2-[5-Chloro-3,4-dimethoxy-2-[2-[4-methoxyphenyl] ethyl]phenyl]ethyl]-N′-[2-phenylethyl]hexane-1,6-diamine dihydrochloride, mp 211-213°;
i) N-[2-[3,4-Dimethoxy-5-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]hexane 1,6-diamine dihydrochloride, mp 199-201°
j) N-[2-[4,5-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-phenylethyl]hexane-1,6-diamine dihydrochloride, mp 196-197.5°;
k) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-methyl-N′-[2-phenylethyl]hexane-1,6-diamine dihydrochloride, softens 138°, mp 148-150°;
l) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenylmethoxy-N′-N′-di[2-phenylethyl]hexane-1,6-diamine dihydrochloride, mp 153.5-155°;
m) N-[2-[3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] phenyl]ethyl]-N′-[2-[4-methoxyphenyl]ethyl]-N′-[2-phenylethyl]hexane-1,6-diamine dihydrochloride hydrate, mp 71-72°.

11. Preparation of 3,4-Dimethoxy-2-[2-[3-methoxyphenyl] ethyl]-N,N-Di-propylbenzeneethanamine hydrochloride

A mixture of 3,4-Dimethoxy-2-[2-[3-methoxyphenyl] ethyl]benzeneethanamine hydrochloride (3.5g), potassium carbonate (6.9g), n-propyliodide (3.9ml) in acetonitrile (120ml) was heated at reflux temperature for 4 hours.
The solution was filtered whilst hot and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water. The organic solution was dried (MgSO₄), filtered and evaporated to give an oil which was purified by flash chromatography (Merck 9385 silica gel) eluting with dichloromethane/5% methanol. The relevant fractions were evaporated to give a colourless oil (2.0g). The oil in ether (20ml) was treated with ethereal hydrogen chloride. The precipitate was filtered and crystallised from isopropanol (1.9g), mp 159-160°.

12. Preparation of 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]-N-[1-methylethyl]benzeneethanamine hydrochloride

a) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl] benzeneacetic acid

A solution of 3,4-Dimethoxy-2-[2-[3-methoxyphenyl] ethyl]benzeneacetonitrile (4.9g) and potassium hydroxide (4.41g) in ethanol (150ml) and water (50ml) was heated under reflux for 18 hours. The mixture was evaporated to dryness and the residue dissolved in water and extracted with ethyl acetate. The organic solution was washed with brine, dried (MgSO₄), filtered and evaporated to leave the sub-title compound as an oil which solidified on trituration with petrol ether (1.72g), mp 77-79°.

b) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]-N-[1-methylethyl]benzeneacetamide

A solution of the acid from step a) (2.18g) and thionyl chloride (0.96ml) in dry dichloromethane (20ml) was heated at reflux temperature for 5 hours. The solution was evaporated to dryness. A solution of the acid chloride in dry dichloromethane (20ml) was added dropwise to an ice-cold solution of isopropylamine (1.12ml) in dry dichloromethane. The solution was stirred at 20° for 16 hours. The reaction mixture was washed with 2N hydrochloric acid, sodium bicarbonate solution and brine, dried (MgSO₄), filtered and evaporated to leave a solid which crystallised from isopropanol to give the sub-title compound as prisms (1.98g), mp 138.5-140°.

c) 3,4-Dimethoxy-2-[2-[3-methoxyphenyl]ethyl]-N-[1-methylethyl]benzeneethanamine hydrochloride

1 M Borane THF complex (25ml) was added dropwise to a stirred solution of the amide of step b) (1.85g) in dry tetrahydrofuran (50ml) under a nitrogen atmosphere. The solution was heated at reflux temperature for 16 hours. The cooled solution was quenched with methanol (50ml) and evaporated to dryness. The residue was dissolved in methanol (50ml) containing concentrated hydrochloric acid (5ml) and the solution heated under reflux for 3 hours. Evaporation gave a solid which crystallised from isopropanol to give the title product as prisms (1.77g), mp 185-186°.

B. Examples

Example 1

4-[2-Aminoethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol

A solution of the product from Intermediate 5 (1.1g) in 48% aqueous hydrobromic acid (15ml) containing hypophosphorous acid (0.1ml) under a nitrogen atmosphere was heated under reflux for 2.5 hours. Evaporation gave the hydrobromide salt of the title compound as a solid which crystallised from isopropanol/ether as prisms (0.8g), mp 154-156°.

Example 2

4-[2-Aminoethyl]-3-[2-[3,5-dihydroxyphenyl]ethyl]-1,2-benzenediol

A 1M solution of boron tribromide in dichloromethane (15ml) was added dropwise to a stirred solution of the benzeneethanamine (1g) in dry dichloromethane (50ml) at -78° under a nitrogen atmosphere. The solution was stirred at 20° for 24 hours. The solution was quenched with methanol (50ml) and evaporated to dryness. The residue was triturated with ether to give 0.8g of the title compound as the hydrobromide salt, mp 222-224°.

Example 3

The following compounds of formula I were prepared by the method of Example 1 from the corresponding intermediates:

3.1)4-[2-Aminoethyl]-3-[2-[4-hydroxyphenyl]ethyl]-1,2-benzenediol, as the hydrobromide salt, mp 214-216°;
3.2)4-[2-Aminoethyl]-3-[2-phenylethyl]-1,2-benzenediol, as the hydrobromide salt, mp 176-177°;
3.3)4-[2-Aminoethyl]-6-chloro-2-[2-[3-hydroxyphenyl] ethyl]-1,2-benzenediol, as the hydrobromide salt, mp 141-143°;
3.4)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-N,N-Di-n-propylaminoethyl]-1,2-benzenediol, as the hydrobromide salt, mp 143-144°;
3.53-[2-[3-Hydroxyphenyl]ethyl]-4-[2-N-1-methylethyl] aminoethyl]-1,2-benzenediol, as the hydrobromide salt, mp 217.5-219°;
3.6)4-[2-Aminoethyl-5-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol, as the hydrobromide salt, mp 182 (decomposes);
3.7)5-[2-Aminoethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol, as the hydrobromide salt, mp 146-148°;
3.8)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[7-[2-phenylethylamino]heptylamino]ethyl]-1,2-benzenediol, as a dihydrobromide, prisms, mp 187-189°;
3.9)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[9-[2-phenylethylamino]nonylamino]ethyl]-1,2-benzenediol, as a dihydrobromide, mp 167-168°;
3.10)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[10-[2-phenylethylamino]decylamino]ethyl]-1,2-benzenediol, as a dihydrobromide, mp 123-125°;
3.11)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]-3-methylpentylamino]ethyl]-1,2-benzenediol, as a dihydrobromide, mp 171-173°;
3.12)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]-3,3-dimethylpentylamino]ethyl]-1,2-benzenediol, as a dihydrobromide, mp 128-130°;
3.13)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]pentylamino]ethyl]-1,2-benzenediol, as a dihydrobromide, mp 171-172°;
3.14)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[N-methyl-N-2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol, as a dihydrobromide hemihydrate, mp 120-122°;
3.15)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[N,N′-di[2-phenylethyl]amino]hexylamino]ethyl]-1,2-benzenediol, as a dihydrobromide hemihydrate, mp 143-145°;
3.16)3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[[2-[4- hydroxyphenyl]ethyl]-[2-phenylethyl]amino]hexylamino]ethyl]-1,2-benzenediol, as a dihydrobromide sesquihydrate, softens 85-87°, mp 120-122°.

Example 4

The following compounds of formula I were prepared by the method of Example 2 from the corresponding Intermediates:

4.1)5-[2-[6-[2-Aminoethyl]2,3-dihydroxyphenyl]ethyl]1,2,3-benzenetriol, as a hydrobromide, mp 225-227°;
4.2)4-[2-Aminoethyl-3-[2-[3,4-dihydroxyphenyl]ethyl]1,2-benzenediol, as a hydrobromide, mp 118-120° (decomposes);
4.3)4-[2-Aminoethyl]-3-[2-[3-nitrophenyl]ethyl]1,2-benzenediol, as a hydrobromide, mp 217-218°;
4.4)N-[3-[2-[6-[2-Aminoethyl]-2,3-dihydroxy]phenyl] ethyl]phenyl]methanesulphonamide, as a hydrobromide, mp 189-191°;
4.5)6-Chloro-3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol, as a dihydrobromide, mp 157-159°;
4.6)6-Chloro-3-[2-[4-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol, as a dihydrobromide, mp 161-164°;
4.7)3-[2-[3-Hydroxyphenyl]ethyl]-5-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol, as a dihydrobromide hemihydrate, mp 60-70°;
4.8)5-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol, as a dihydrobromide hemihydrate, mp 120-150° (decomposes);
4.9)4-[2-Aminoethyl]-6-chloro-2-[2-[4-hydroxyphenyl] ethyl]-1,2-benzenediol, as the hydrobromide salt, softens 128-130°, mp 162-164°.

Example 5

3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-hydroxy-2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol

a) 6-[2-[3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy] phenyl]ethyl]phenyl]ethylamino]-6-oxohexanoic acid

A solution of monomethyladipate (0.74ml) and triethylamine (0.69ml) in dry dichloromethane (50ml) was stirred at 0° during the dropwise addition of a solution of ethyl chloroformate (0.48ml) in dry dichloromethane (20ml). The mixture was stirred under an atmosphere of nitrogen at 0° for 30 minutes and a solution of 3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy]phenyl]ethyl] benzeneethanamine (2.70g) in dry dichloromethane (50ml) was then added. The mixture was stirred at 20° for 18 hours.
The reaction mixture was washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, water, dried (MgSO₄), filtered and evaporated. Crystallisation from petrol ether 60/80 gave the intermediate ester (2.87g) as a colourless solid, mp 120-121°.
A solution of the ester (2.87g) in methanol (30ml) and 10% potassium hydroxide solution (5ml) was heated at reflux temperature for 3 hours. The solution was evaporated and the residue acidified with 2N hydrochloric acid. The solid mass was dissolved in ethyl acetate (200ml), washed with water, dried (MgSO₄), filtered and evaporated to give a solid. Crystallisation from ethyl acetate/60:80 petrol ether gave the sub-title acid as colourless prisms, mp 160-162°.

b) N-[2-Hydroxy-2-phenyl]ethyl-N′-[2-[3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy)phenyl]ethyl] phenyl]hexane-1,6-diamide

A solution of the product from step a) (2.41g) and N,N-carbonyldiimidazole (0.583g) in dry dichloromethane (50ml) was stirred at 20° under nitrogen for 2 hours and a solution of 2-amino-1-phenylethanol (0.54g) in dry dichloromethane (20ml) was then added. The mixture was stirred at 20° for 16 hours. Chloroform (50ml) was added and the mixture washed with 2N hydrochloric acid, saturated sodium bicarbonate, water, dried (MgSO₄), filtered and evaporated to give a solid. Crystallisation from chloroform/petrol ether 40/60 gave the intermediate diamide as a colourless powder (1.64g), mp 196-197°.

c) N-[2-Hydroxy-2-phenyl]ethyl-N′-[2-[3,4- Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy)phenyl]ethyl] phenyl]hexane-1,6-diamine

A solution of the diamide intermediate from step b) (1.5g) in dry tetrahydrofuran (30ml) was stirred under an atmosphere of nitrogen during the addition of a 1M solution of borane in tetrahydrofuran (10ml). The mixture was heated to reflux temperature for 24 hours.
Methanol (50ml) was added to the cooled solution and the mixture evaporated to dryness. The residue was dissolved in methanol (50ml) and concentrated hydrochloric acid (5ml) added. The solution was stirred at 20° for 5 hours. The solution was evaporated to give a solid which crystallised from isopropanol to give 1.25g of the dihydrochloride monohydrate salt of the sub-title compound, mp 192-194°.

d) 3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-hydroxy-2-phenylethylamino]1hexylamino]ethyl]-1,2-benzenediol

A solution of the diamine intermediate from step c) (1.5g) in methanol (50ml) containing a 10% Palladium on charcoal catalyst (0.15g) was hydrogenated at 45 psi for 18 hours. The catalyst was removed by filtration and the solution evaporated to give an oil. Trituration with hot isopropanol then ether gave a colourless solid (0.81g). The solid was purified by semi-preparative reverse phase HPLC (Dynamax-60A column) eluting with water with 0.1% trifluoroacetic acid/methanol (1:1) to give after evaporation (0.48g) of the hydrochloride trifluoroacetate hemihydrate mixed salt of the title compound, mp decomposes 100°.

Example 6

3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[7-[2-phenylethylamino]-4-hydroxyheptylamino]ethyl]-1,2-benzenediol

a) N-[2-Phenylethyl]-2,3,4,5-tetrahydro-5-oxo-2-furanpropanamide

A solution of 2,3,4,5-tetrahydro-5-oxo-2-furanpropanoic acid (7.9g) and N,N-carbonyldiimidazole (8.1g) in dry dichloromethane (100ml) was stirred under nitrogen at 20° for 30 minutes and a solution of 2-phenylethylamine (6.05g) in dry dichloromethane (20ml) was then added. The mixture was stirred at 20° for 2 hours. The solution was washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, water, dried (MgSO₄), filtered and evaporated to give an oil which solidified on standing. Crystallisation from toluene gave the amide as fluffy crystals (10.4g), mp 86-87°.

b) N-[2-[3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy] phenyl]ethyl]phenyl]ethyl]-N′-[2-phenylethyl]-4-hydroxy heptane-1,7-diamide

A solution of the intermediate step a) (1.3g) and 3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy)phenyl]ethyl] benzeneethanamine (5.3g) in dry xylene (100ml) was heated to reflux temperature for 5 hours. Evaporation and trituration of the residue with ether gave the impure amide as a beige solid (2.5g). The solid was purified by flash chromatography (Merck 9385 Silica gel) eluting with chloroform 20% methanol to give the sub-title compound as a beige solid (2g), mp 132-133°.

c) N-[2-[3,4-Di(phenylmethoxy)-2-[2-[3-(phenylmethoxy] phenyl]ethyl]phenyl]ethyl]-N′-[2-phenylethyl]-4-hydroxy heptane-1,7-diamine

A solution the diamide intermediate step b) (2g) in dry tetrahydrofuran (50ml) was stirred under an atmosphere of nitrogen during the addition of a 1M solution of borane in tetrahydrofuran (15ml). The mixture was heated to reflux temperature for 16 hours. Methanol (50ml) was added to the cooled solution and the mixture evaporated to dryness. The residue was dissolved in methanol (20ml) and concentrated hydrochloric acid added (2ml). The solution was stirred at room temperature for 16 hours. The precipitate was filtered and the solid crystallised from methanol to give 1.6g of the dihydrochloride salt of the sub-title compound, mp 221-223°.

d) 3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[7-[2-phenylethylamino]-4-hydroxyheptylamino]ethyl]-1,2- benzenediol

A solution of the diamine intermediate from step c) (1.55g) in methanol (150ml) was hydrogenated over a 10% Palladium on charcoal catalyst (0.15g) at atmospheric pressure for 24 hours.
The catalyst was removed by filtration and the filtrate evaporated to leave 0.85g of the dihydrochloride hydrate salt of the title compound, mp 64-66° decomposes.

Claims

1. A process for the preparation of a compound of formula I,

in which
one of R₃₀ and R₄₀ represents a group Ra,

wherein X represents a C2 to C8 alkylene chain optionally interrupted by a double bond or by S(0)_n, wherein n is 0, 1 or 2, Z represents a C 1 to C3 alkylene chain, each of X and Z being optionally substituted by OH or one or more alkyl C 1 to C6,
R₇₀ represents hydrogen, alkyl C 1 to C6 or (CH₂)_qR₁₁,
R₁₀ and R₁₁ independently represent phenyl substituted by one or more substituents R₂₃, which may be the same or different; or R₁₀ represents a saturated carbocyclic group,
R₁₅ represents hydrogen, alkyl C 1 to C6, or together with R₂₃ forms a (CH₂)p chain, wherein p represents 0, 1 or 2,
R₂₀, R₂₁, R₂₂ and R₂₃ independently represent hydrogen, alkyl C 1 to C6, NHR₂₅, SH, NO₂, halogen, CF₃, SO₂R₂₆, CH₂OH or OH, wherein R₂₅ represents hydrogen, alkyl C 1 to C6 or alkanoyl C 1 to C6 and R₂₆ represents alkyl C 1 to C6 or NH₂
l represents 2, 3 or 4,
q represents an integer from 1 to 6 inclusive,
provided that when R₄₀, R₅₀ and R₇₀ each represent hydrogen and R₆₀ represent Rb,
then Ra represents 2(3-hydroxyphenyl)ethyl, R₁₅ represents hydrogen and either
a) X represents (CH₂)_p, in which p is 3, 5, 7 or 8 or
b) at least one of X and Z is substituted by either OH or one or more alkyl C 1 to C6,
and pharmaceutically acceptable salts and solvates thereof, which comprises removing a protecting group from a corresponding compound of formula II,

in which
R₃₀a and R₄₀a have the same significance, respectively, as R₃₀ and R₄₀ as defined above, save that in addition one of R₃₀a and R₄₀a may represent a group R_al,

R₅₀a has the same significance as R₅₀ above, save that in addition it may represent R₃a,
R₆₀a has the same significance as R₆₀ above, save that in addition it may represent a group R_bl,

in which
Xa and Za have the same significance, respectively, as X and Z above, save that in addition each may be substituted by OR₆a,
R₇₀a has the same significance as R₇₀ above, save that in addition it may represent R₄a or (CH₂)_qR₁₁a,
R₁₀a and R₁₁a have, respectively, the same significance as R₁₀ and R₁₁ above, save that when R₁₀a or R₁₁a represents phenyl, it may be substituted by one or more substituents R₂₃a,
R₁a, R₂a, R₃a and R₄a, which may be the same or different, represent hydrogen or a protecting group,
R₂₀a, R₂₁a R₂₂a and R₂₃a, respectively, have the same significance as R₂₀, R₂₁, R₂₂ and R₂₃ above, save that in addition they may represent NR₂₅R₂₇a, SR₂₈a, CH₂OR₂₉a or OR₃₁a, wherein R₂₇a, R₂₈a, R₂₉a and R₃₁a, which may be the same or different, each represents a protecting group, and R₁₅, R₂₅, l and q are as defined above, provided that the compound of formula II bears at least one protecting group,
and where desired or necessary converting the resulting compound of formula I to a pharmaceutically acceptable salt or solvate thereof, or vice versa.

2. A process according to Claim 1, wherein R₃₀ represents Ra.

3. A process according to Claim 1 or 2, wherein R₄₀ represents hydrogen.

4. A process according to any one of the preceding claims, wherein R₅₀ represents hydrogen.

5. A process according to any one of the preceding claims, wherein R₆₀ represents hydrogen.

6. A process according to any one of the preceding claims, wherein at least one of R₂₀, R₂₁ and R₂₂ represents hydroxy.

7. A process according to any one of the preceding claims, wherein at least one of R₂₀, R₂₁ or R₂₂ represents 3-hydroxy.

8. A process according to Claim 1, wherein the compound of formula is
4-[2-Aminoethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol
4-[2-Aminoethyl]-3-[2-[3,5-dihydroxyphenyl]ethyl]-1,2-benzenediol
4-[2-Aminoethyl]-3-[2-[4-hydroxyphenyl]ethyl]-1,2- benzenediol
4-[2-Aminoethyl]-3-[2-phenylethyl]-1,2-benzenediol
4-[2-Aminoethyl]-6-chloro-2-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-N,N-Di-n-propylaminoethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-N-1-methylethyl] aminoethyl]-1,2-benzenediol
4-[2-Aminoethyl]-5-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol
5-[2-Aminoethyl]-3-[2-[3-hydroxyphenyl]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl-4-[2-[7-[2-phenylethylamino]heptylamino]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[9-[2-phenylethylamino]nonylamino]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[10-[2-phenylethylamino]decylamino]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]-3-methylpentylamino]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2-phenylethylamino]-3,3-dimethylpentylamino]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[5-[2- phenylethylamino]pentylamino]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[N-methyl-N-2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-[N,N′-di-[2-phenylethyl]amino]hexylamino]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[[2-[4-hydroxyphenyl]ethyl]-[2-phenylethyl]amino]hexylamino]ethyl]1,2-benzenediol
5-[2-[6-[2-Aminoethyl]2,3-dihydroxyphenyl]ethyl]1,2,3-benzenetriol
4-[2-Aminoethyl]-3-[2-[3,4-dihydroxyphenyl]ethyl]1,2-benzenediol
4-[2-Aminoethyl]-3-[2-[3-nitrophenyl]ethyl]1,2-benzenediol
N-[3-[2-[6-[2-Aminoethyl]-2,3-dihydroxy]phenyl]ethyl] phenyl]methanesulphonamide
6-Chloro-3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol
6-Chloro-3-[2-[4-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-5-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol
5-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-phenylethylamino]hexylamino]ethyl]1,2-benzenediol
4-[2-Aminoethyl]-6-chloro-2-[2-[4-hydroxyphenyl]ethyl] 1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[6-[2-hydroxy-2-phenylethylamino]hexylamino]ethyl]-1,2-benzenediol
3-[2-[3-Hydroxyphenyl]ethyl]-4-[2-[7-[2-phenylethylamino]-4-hydroxyheptylamino]ethyl]-1,2-benzenediol
or a pharmaceutically acceptable salt or solvate thereof.